The purpose of this study is to determine the safety and tolerability of PA-824 when given with a single dose of midazolam, and to determine whether PA-824 inhibits CYP3A to a clinically important degree as measured by the effect of PA-824 on the pharmacokinetics of midazolam, a known CYP3A substrate.

Further study details as provided by Global Alliance for TB Drug Development:

Primary Outcome Measures:

Evaluate the effects of multiple-dose administration of PA-824 on the pharmacokinetics of midazolam, a sensitive probe substrate and representative compound for drugs metabolized by CYP3A enzymes. [ Time Frame: Day 18 ] [ Designated as safety issue: No ]

The PK parameters to be calculated for midazolam and 1-hydroxy midazolam include area under the curve [AUC(0-t) and AUC(0-inf)], maximum observed concentration (Cmax), time to maximum observed plasma concentration (Tmax), half-life (t1/2), and apparent terminal elimination rate constant (Kel).

To evaluate the safety and tolerability of PA-824 when given with midazolam. [ Time Frame: Day 108 ] [ Designated as safety issue: No ]

This study is an open-label, fixed sequence design. 14 subjects will receive a single dose of 2 mg midazolam, followed by a 2-day wash-out. Following the wash-out, all subjects will receive PA-824 once daily for 14 days. All patients will receive a single dose of 2 mg midazolam on the 14th day of PA-824 dosing. This study will evaluate 400 mg PA-824.

Eligibility

Ages Eligible for Study:

19 Years to 50 Years (Adult)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Have the ability to understand the requirements of the study, have provided written informed consent (as evidenced by signature on an informed consent document approved by an IRB), and agree to abide by the study restrictions.

Be healthy non-tobacco/nicotine using (6-month minimum) adult subjects, 19 to 50 years of age, inclusive.

Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death (such as known coronary artery disease or CHF or terminal cancer)

At either Screening or the pre-dose read before the first dose, a QTcB (Bazett's correction) >450ms for men and women, calculated from the average of triplicate reads collected at the screening and predose sitting.

At either Screening or the pre-dose read before the first dose, a QTcF (Fridericia's correction) >450ms for men and women, calculated from the average of triplicate reads collected at the screening and predose sitting.

History of hypokalemia or hypomagnesemia.

History or presence of alcoholism or drug abuse within the past 2 years (as deemed by the Principal Investigator).

Use of alcohol within 72 hours prior to dosing.

Significant history of drug and/or food allergies (as deemed by the Principal Investigator).

For women, subject is pregnant (positive test for serum HCG at Screening or Check-in), breastfeeding or planning to conceive a child within 30 days of cessation of treatment.

For males, planning to father a child within 12 weeks of cessation of treatment.

History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination.

Specific Treatments

Any contraindication to the use of nitroimidazoles, or prior treatment with PA-824 or OPC-67683.

Use of any systemic or topical prescription medication within 14 days prior to dosing or during the study, except hormonal contraceptives in women.

Use of any systemic or over-the-counter medication including vitamins, herbal preparations, antacids, cough and cold remedies, etc., within 7 days prior to dosing or during the study treatment periods.

Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine, etc.) within 30 days prior to dosing.

Consumption of products containing grapefruit within 10 days prior to dosing.

Any special dietary changes during the 30 days prior to dosing, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.

Any strenuous exercise within 7 days of Check-in, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.

Donation of whole blood or significant loss of blood within 56 days prior to dosing.

Plasma donation within 7 days prior to dosing.

Participation in another interventional clinical trial within 30 days prior to dosing.

Based on Lab Abnormalities

Any serum creatinine or BUN measure beyond the upper limit of the normal range at Screening or Check-in. Individual values may be discussed with the Sponsor Medical Monitor.

Hemoglobin < 12.0 g/dL at the screening visit.

Positive Screening test for HCV, HBV, or HIV.

Any other factor which suggests to the Principal Investigator that the subject should not participate in the study.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01768273